Valproate is a broad spectrum antiepileptic and anticonvulsive agent. Valproic acid is liquid at room temperature and thus not suitable for manufacturing of solid dosage forms, e.g., tablets for oral administration. Sodium valproate is solid, but an extremely hygroscopic, deliquescent substance. It absorbs water from the atmosphere already during tabletting, resulting in problems of tablet production, like sticking to the punches.
A valproic cid-sodium valproate 1:1 complex (divalproex sodium) is described in U.S. Pat. No. 5,212,326 and WO 96/23491. It is a solid at room temperature and is described to be nonhygroscopic.
To eliminate the extreme tendency to deliquescence, various methods have been recommended. One possibility is the hydrophobic coating of the tablets (Yamatogi, Yasuko; Yokhinaga, Harimi; Oka, Eiji; Ohtahara, Shunsuke; Yamashita, Syoichi; Furuno, Katsushi; Gomita, Yutaka, Psychiatry Clin. Neurosci. (1995), 49(3), S245-S247 (Chem. Abstr.:23:217657)). Another way is to use the prodrug of valproic acid, valpromide, a primary amide of valproic acid, which is a solid, neutral, non-hygroscopic material having several pharmaceutical advantages over valproic acid or sodium valproate (Bialer, Meir, Trends, Med. Chem. '90, Proc. Int. Symp. Med, Chem., 11.sup.th (1992), 337-81. Editor(s): Sarel, Shalom; Mechoulam, Raphael; Agranat, Israel. Publisher:Blackwell, Oxford, UK.)
It has been found by the inventors that granulation of sodium valproate leads to a water content of more than 2%. This results in extreme technical problems of further processing the granules, e.g., in order to produce the compression mass and to tablet the mass. Problems are sticking to the punches and an increase of rejection force of the lower punch, stopping the tabletting machine. A too dry compression mass leads to capping of the tablets while sticking is reduced. That means when sodium valproate is granulated with, e.g.,. lactose, the absolute humidity of the compression mass should not be above 2% to be successfully tabletted after granulation. To enable production, usually high technical efforts have to be made and expensive equipment is necessary, like air conditioning to low relative moisture.
It is further known that inclusion complex formation with cyclodextrins can suppress the deliquescence of sodium valproate (JP 56133236). The effective molar ratio of sodium valproate/cyclodextrin complex is claimed to be in the range of 1:0.1 to 1:2. This is, however, technically not feasible because the daily dose of valproate is 2 g, i.e., to this dose 1.4 g to 28 g .beta.-cyclodextrin would be necessary, which--taking into account the further inevitable tablet ingredients, like binding, gliding, disintegrating additives would result in unacceptable large tablets.
The object of the invention is to provide solid formulations of sodium valproate with increased stability to deliquescence, to pharmaceutical formulations with high sodium valproate content and to processes with improved technical handling features to prepare the same.
According to the present invention, it has surprisingly been found that cyclodextrins are effective in decreasing the deliquescence of sodium valproate, by forming a composition of sodium valproate with cyclodextrin at a molar ratio of 1:0.01 to 1:0.09, preferably at a molar ratio of 1:0.02 to 1:0.05. In this case, only one cyclodextlin molecule to about 25-50 valproate molecules is necessary to prevent the deliquescence of the drug. This amount of cyclodextrin is not enough to clathrate the drug. The inclusion complex formation is practically not detectable, and the cyclodextrin behaves as an unusual antideliquescence carrier in the solid dispersion.
According to the present invention, the first three members of cyclodextrin homologues, that is .alpha.-, .beta.-or y-cyclodextrin can be used.
In the embodiments of the present invention, the solvent evaporation method is applied, preferably with water. The use of any other solvent of sodium valproate (e.g., ethanol, dimethyl sulfoxide) is limited because particular attention has to be devoted to the removal of the residual solvent that may be toxic and environmental polluting at the production. Generally, their presence is not tolerated in the finished product. As cyclodextrins form inclusion complexes with most of these solvents, the removal of last traces might be difficult.
The solid dispersion according to the invention can be prepared by the following methods:
Solution method:
Sodium valproate and a water soluble cyclodextrin are dissolved in water. The solution is stirred thoroughly and water is removed by evaporation or freeze drying or spray drying to obtain the solid dispersion.
Suspension method:
Sodium valproate is dissolved in water and .beta.-cyclodextrin is suspended in the valproate solution. The solid dispersion is obtained by freeze drying or spray drying.
Kneading method:
The components are well mixed, then wetted with water, kneaded thoroughly at 0-80.degree. C. and dried in an oven at 40-110.degree. C. It has further been found that the solid dispersion of the invention has improved technological properties, showing enhanced flowability, tabletability and stability to moisture. Especially with respect to the stability to moisture, the solid dispersion shows features that enable a granulation and tabletting process with an absolute moisture content of about 3-5%.
The advantage of the present invention is that using cyclodextrins, in far less than the stoichiometric ratio (i.e., without formation of inclusion complex) the obtained product is non-deliquescent and has improved handling and processing characteristics. Sodium valproate itself can only be tabletted, if air conditioning to low relative humidity and/or anti adhesive coating of the punches and other expensive and non standard measures during routine tablet production are applied, because of the poor flowing and high sticking to the tabletting machine of the tabletting masses with a high concentration of the active ingredient. Using as low as 10-40 weight percent .beta.-cyclodextrin (equivalent to 1:0.01 to 1:0.09 drug to cyclodextrin molar ratio) the product has improved flowing and ejection properties, even in the presence of 3-5% of loss drying of the compression mass.
In contrast to complexes formed by equimolar amounts of sodium valproate and cyclodextrin dosage forms can be prepared having a sodium valproate content of 50 to 90% by weight. Usually single dose tablets contain 300 to 600 mg sodium valproate. According to the invention, tablets having a total weight of 500 to 950 mg can be prepared. Moreover, the solid dispersion is also suitable for direct tabletting.
The granulation process can be done by standard methods, e.g., fluid bed or wet granulation. The solid dispersion will granulate together with usual excipients like polyvinylpyrrolidone, silicon dioxide, cellulose esters, cyclodextrins, etc. The granulate will be further processed to tablets by employing usual techniques, and may also contain cyclodextrin as further excipient. The tablets may further be enteric coated.
The solid dispersion can further be used for the preparation of sustained release compositions. The sustained release compositions can be obtained with hydrogel matrices like HPMC, alginic acid, and/or salts thereof, and/or polyacrylates such as Eudragit.RTM. and may, in addition, contain a pharmaceutically acceptable organic acid such as citric acid, tartaric acid or succinic acid or salts of these acids.
The following examples are presented to further illustrate the present invention.